Sharma Deepti K, Cheok Tim Soon, Rogers Manuela, Zhe Lu Victor Yan, Solomon Lucian B, Ramasamy Boopalan, Clifton Peter M, Callary Stuart A
Centre for Orthopaedic and Trauma Research, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia; Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, SA, Australia.
Department of Orthopaedic and Trauma Surgery, Flinders Medical Centre, Adelaide, SA, Australia; Department of Orthopaedic Surgery, The Prince Charles Hospital, Chermside, Queensland, Australia.
Clin Nutr ESPEN. 2025 Aug;68:790-805. doi: 10.1016/j.clnesp.2025.06.034. Epub 2025 Jun 20.
Patients with elevated homocysteine (Hcy) levels are associated with an increased risk of fracture. B-vitamin supplementation studies have consistently shown an ability to reduce Hcy levels but have had no or marginal effect on bone mineral density (BMD), which led us to hypothesize that hyperhomocysteinemia may increase fracture risk by altering bone quality outcome measures beyond BMD. The aim of our systematic review was to investigate the association between Hcy and bone quality outcome measures, i.e. bone turnover, bone microarchitecture, collagen crosslinks and micro damage accumulation, in healthy adults.
A systematic search was performed on Pubmed, Embase, and Scopus from the date of inception to 30th of September 2024. Studies were included that had sufficient data to identify the pooled relationship between plasma Hcy and at least one domain of bone quality, such as bone microarchitecture, bone turnover, advanced glycation product (AGE) pentosidine levels, collagen crosslinks, or micro damage accumulation. Studies involving patients who were on medications or had conditions affecting plasma Hcy or bone health were excluded. Osteoporotic patients were included only if they had not been treated.
Twenty-seven studies were included in our systematic review. Our meta-analysis found a significant positive correlation between Hcy and osteocalcin [Pearson's coefficient of correlation (r) = 0.39, significance value (p) = 0.023, 95 % Confidence Interval (CI) = 0.36-0.42]. No significant correlation was observed between Hcy and Procollagen type-1 N propeptide (P1NP), C-terminal telopeptide of type 1 collagen (CTX-1), or Bone-specific alkaline phosphatase (Bone ALP). Additionally, we found a strong positive correlation between Hcy and the AGE serum pentosidine [r = 0.72; 95 % CI: 0.67-0.76; p = 0.020], a molecule linked to increased non-enzymatic collagen cross-linkage. Further, two studies measured collagen-crosslinking in the bone, and both reported elevated Hcy to be associated with higher non-enzymatic crosslinks and reduced enzymatic crosslinks.
Our results suggest that elevated Hcy impacts bone quality outcome measures. The effect is possibly mediated via increased bone turnover and accumulation of non-enzymatic collagen crosslinking, resulting in decreased bone strength.
CRD42024595870.
同型半胱氨酸（Hcy）水平升高的患者骨折风险增加。补充B族维生素的研究一直表明其有降低Hcy水平的能力，但对骨密度（BMD）没有影响或仅有微小影响，这使我们推测高同型半胱氨酸血症可能通过改变除BMD之外的骨质量指标来增加骨折风险。我们系统评价的目的是研究健康成年人中Hcy与骨质量指标（即骨转换、骨微结构、胶原交联和微损伤积累）之间的关联。
对PubMed、Embase和Scopus从创刊至2024年9月30日进行系统检索。纳入的研究需有足够数据来确定血浆Hcy与至少一个骨质量领域（如骨微结构、骨转换、晚期糖基化终产物（AGE）戊糖苷水平、胶原交联或微损伤积累）之间的汇总关系。排除涉及正在服用药物或患有影响血浆Hcy或骨骼健康疾病的患者的研究。仅纳入未接受治疗的骨质疏松症患者。
27项研究纳入我们的系统评价。我们的荟萃分析发现Hcy与骨钙素之间存在显著正相关[皮尔逊相关系数（r）=0.39，显著性值（p）=0.023，95%置信区间（CI）=0.36 - 0.42]。未观察到Hcy与I型前胶原N端前肽（P1NP）、I型胶原C端肽（CTX - 1）或骨特异性碱性磷酸酶（骨ALP）之间存在显著相关性。此外，我们发现Hcy与AGE血清戊糖苷之间存在强正相关[r = 0.72；95% CI：0.67 - 0.76；p = 0.020]，AGE血清戊糖苷是一种与非酶促胶原交联增加相关的分子。此外，两项研究测量了骨中的胶原交联，均报告Hcy升高与更高的非酶促交联和更低的酶促交联相关。
我们的结果表明Hcy升高会影响骨质量指标。这种影响可能是通过增加骨转换和非酶促胶原交联积累介导的，从而导致骨强度降低。
PROSPERO注册号：CRD42024595870。
